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Antihypertensive Therapy in the Presence of Proteinuria

Pantelis A. Sarafidis, MD, PhD, Nitin Khosla, MD, and George L. Bakris, MD

The presence of proteinuria is a well-known risk factor for both the progression of renal disease andcardiovascular morbidity and mortality, and decreases in urine protein excretion level were associatedwith a slower decrease in renal function and decrease in risk of cardiovascular events. Increased bloodpressure has a major role in the development of proteinuria in patients with either diabetic or nondiabetickidney disease, and all recent guidelines recommend a blood pressure goal less than 130/80 mm Hg inpatients with proteinuria to achieve maximal renal and cardiovascular protection. Drugs interfering withthe renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptorblockers, should be used as first-line antihypertensive therapy in patients with proteinuria because theyseem to have a blood pressure–independent antiproteinuric effect, and if blood pressure levels are stillout of goal, a diuretic should be added to this regimen. A combination of an angiotensin-convertingenzyme inhibitor with an angiotensin receptor blocker or other classes of medications shown todecrease protein excretion, such as nondihydropyridine calcium antagonists or aldosterone receptorblockers, should be considered to decrease proteinuria further. This review provides an extendedsummary of current evidence regarding the associations of blood pressure with proteinuria, the rationalefor currently recommended blood pressure goals, and the use of various classes of antihypertensiveagents in proteinuric patients.Am J Kidney Dis 49:12-26. © 2006 by the National Kidney Foundation, Inc.

INDEX WORDS: Proteinuria; kidney disease; hypertension; angiotensin-converting enzyme (ACE)inhibitors; angiotensin-receptor blockers (ARBs).

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normally functioning kidney will excrete asmall amount of protein in urine. The compo-

ition of this protein excretion is about 20% low-olecular-weight proteins, 40% Tamm-Horsfallucoprotein secreted by the distal tubules, and

0% high-molecular-weight albumin.1 The first 2ypes of protein are not detectable using conven-ional dipsticks, but albumin is measured routinelyn the evaluation of abnormal urinary protein excre-ion. Urinary albumin excretion (UAE) rates be-ween 30 and 300 mg/d (0.03 and 0.3 g/d) if

From the Hypertension/Clinical Research Center, Depart-ent of Preventive Medicine, Rush University Medical Cen-

er, Chicago, IL.Received August 14, 2006; accepted in revised form

ctober 11, 2006.Originally published online as doi:10.1053/j.ajkd.2006.10.014

n December 1, 2006.Support: None. Potential conflicts of interest: None.Address reprint requests to George L. Bakris, MD,

rofessor of Medicine, Director, Hypertension Unit, Sec-ion of Endocrinology, Diabetes & Metabolism, Universityf Chicago-Pritzker School of Medicine, 5841 S Marylandve, MC 1027, Rm #P-328A, Chicago, IL 60637. E-mail:bakris@earthlink.net© 2006 by the National Kidney Foundation, Inc.0272-6386/06/4901-0004$32.00/0

tdoi:10.1053/j.ajkd.2006.10.014

American Journal o2

easured in a 24-hour urine collection, 20 and 200g/min (34 � 10�8 to 34 � 10�7 g/s) if measured

n a timed urine collection, or 30 and 300 mg/g0.03 and 0.3 g/g) if measured with the use ofrinary albumin-creatinine ratio in a spot urineollection are characterized as microalbuminuria,hereas every albumin or protein excretion greater

han these levels represents albuminuria or clinicalroteinuria (Table 1).2,3 Although current knowl-dge suggests that microalbuminuria be considereds a marker of abnormal vascular function and riskactor for cardiovascular disease,4 proteinuria is aypical manifestation of overt nephropathy and isssociated with both faster deterioration in kidneyunction and increased risk of cardiovascular dis-ase.5,6

In the general population, the prevalence ofroteinuria is low. For example, in the US adultopulation, it was estimated at around 1.3%,anging from 1% in white individuals to 2.4% inlack individuals.7 However, proteinuria appearsore often with increasing age (�3.9% in people70 years)7 and is much more common in indi-

iduals with hypertension or diabetes.8 For ex-mple, without specific interventions, 80% ofatients with type 1 diabetes and 20% to 40% of

hose with type 2 diabetes and microalbuminuria

f Kidney Diseases, Vol 49, No 1 (January), 2007: pp 12-26

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Antihypertensive Treatment in Proteinuria 13

ill progress to macroalbuminuria during 10 to5 years.3

Hypertension is a well-recognized cause ofhronic kidney disease, and blood pressure (BP)evel directly influences the development of pro-einuria.2 Conversely, hypertension can be a con-equence of kidney disease because many abnor-alities present in an individual with nephropathy

ould result in BP elevation.9 Interventions thatecrease BP levels in patients with proteinuriand mild-to-moderate renal insufficiency consis-ently were shown to slow the progression ofidney disease.10 According to the National Kid-ey Foundation–Kidney Disease Outcomes Qual-ty Initiative Working Group guidelines, the goalsf antihypertensive therapy in patients withhronic kidney disease are to decrease BP, asell as decrease the risk of cardiovascular dis-

ase and slow the progression of kidney diseasen patients with or without hypertension.2 Be-ause proteinuria is associated with both risk ofardiovascular disease and progression to end-tage renal disease (ESRD) and decreases inroteinuria correlate with decreases in cardiovas-ular morbidity and mortality and preservationf kidney function,11 changes in urinary proteinxcretion level would best reflect the effect ofntihypertensive treatment in these patients.

This review discusses the natural history ofroteinuria development in relation to abnormalP levels, the rationale for currently recom-ended BP goals in patients with proteinuria,

nd the evidence for the various nonpharmaco-ogical and pharmacological approaches tochieve these goals.

THE NATURAL HISTORY OF PROTEINURIA

When evaluating the natural history of protein-

Table 1. Definitions of Microalbumin

Urine Collection Method

lbumin 24-Hour collection (mg/d)Timed collection (�g/min)Spot urine albumin-creatinine ratio (mg/g)

otal protein 24-Hour collection (mg/d)Timed collection (�g/min)Spot urine protein-creatinine ratio (mg/g)

Note: Modified from the National Kidney Foundation–Kidssociation guidelines.3 To convert albumin or total proteg/min to g/s, multiply by 0.000000017; albumin- or total pr

ria, a distinction must be made between those d

ith and without diabetes mellitus. Previoustudies of patients with type 1 diabetes showedhat average time from diagnosis of diabetes tohe development of proteinuria is 19 years, andhe strongest predictor of proteinuria is the pres-nce of microalbuminuria.12,13 This close associa-ion between the presence of microalbuminuriand subsequent development of proteinuria inatients with type 1 diabetes was supported fur-her from additional data and, for some years,as considered a definite finding.14 However,

ecent evidence showing that 64% of patientsith type 1 diabetes and microalbuminuria re-erted to normoalbuminuria within 5 years15

hallenges the predictive value of microalbumin-ria, and the issue needs to be examined further.n patients with type 2 diabetes, although somevidence relating microalbuminuria to protein-ria development exists, the natural history ofroteinuria seems more variable.16 For example,n a large prospective study from Italy, microalbu-

inuria increased the risk of developing overtephropathy by 42%, but other factors, ie, levelf glycemic control, were strongly predictive ofroteinuria development.17

It is important to note that the occurrence ofypertension in relation to abnormal urinary pro-ein excretion is different in patients with type 1nd type 2 diabetes. Patients with type 1 diabetesave increases in systolic and diastolic BP onlyfter the development of microalbuminuria, andhese increases could act as an aggravating fac-or, whereas isolated systolic hypertension with-ut microalbuminuria has not been predictive ofvert nephropathy. Conversely, in patients withype 2 diabetes, increases in BP usually precedend can predict the development of abnormalrinary protein excretion.18,19 Overall, relevant

nd Macroalbuminuria or Proteinuria

rmal Microalbuminuria Albuminuria or Clinical Proteinuria

30 30-299 �30020 20-199 �20030 30-299 �300

300 Not applicable �30020 Not applicable �200

200 Not applicable �200

ease Outcomes Quality Initiative2 and American Diabetesg/d to g/d, multiply by 0.001; albumin or total protein in

reatinine ratio in mg/g to g/g, multiply by 0.001.

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ype 1 diabetes can reflect continuous damage tohe kidney, beginning with microalbuminuria thatelates to incipient nephropathy and ending withroteinuria, whereas in patients with type 2 dia-etes, abnormal UAE relates primarily to athero-clerotic vascular damage, and varying levels oflood glucose and BP help explain the differentourses of nephropathy among different patients.

The natural history of proteinuria in patientsith nondiabetic renal disease is much less wellefined; the most likely explanation is variedauses of nondiabetic renal disease. However,P levels also directly influence the develop-ent of proteinuria. In a study of 387 hyperten-

ive patients, UAE levels were directly propor-ionate to systolic, diastolic, and mean BPeasured at the office or with an ambulatoryonitor.20 A population study with 1,567 partici-

ants showed an 18–mm Hg higher systolic BPn the group of nondiabetic individuals with

icroalbuminuria than in those without mi-roalbuminuria.21 In addition, proteinuria clearlyorrelates with renal function impairment. Thisas shown by a study of 7,728 individuals with-ut diabetes that stratified subjects into 4 differ-nt groups based on baseline albumin excretion:ormal (0 to 15 mg/d), high normal (15 to 30g/d), microalbuminuria (30 to 300 mg/d), andacroalbuminuria (�300 mg/d). The macroalbu-inuria group had a decrease in glomerularltration rates (GFRs), whereas the high-normalnd microalbuminuria groups had increases inFRs.22 The explanation for these findings re-

ates to the pathophysiological process of renalunction loss in patients with nondiabetic kidneyisease.23 When an insult initiates renal injurynd abnormal UAE, the kidney responds byypertrophying and hyperfiltering. Initially, thisllows the kidney to meet the body’s demands,ut it leads to a vicious circle because hyperfilter-ng will increase protein leakage, which leads toncreased renal damage and loss of moreephrons. The final result of this cascade is bothroteinuria and a decrease in GFR.

ROLE OF PROTEINURIA IN SETTINGBP GOALS

All recent relevant guidelines recommend aP goal less than 130/80 mm Hg for patientsith diabetes and/or chronic kidney dis-

ase.2,3,24,25 In patients with diabetes, the rel- w

vant evidence derives mainly from 2 outcomerials that randomly assigned subjects to differentP levels, the Hypertension Optimal Treatment

rial26 and the United Kingdom Prospective Diabe-es Study (UKPDS) 38,27 which showed significantecreases in cardiovascular mortality in the groupsf patients with diabetes that achieved the lower BPevels. However, it should be noted that in the onlytudy with renal end points that included patientsith diabetes and showed a benefit with a low BPoal, the population largely consisted of patientsith nondiabetic kidney disease.28 Thus, there cur-

ently is no evidence in favor of a low BP goal toeduce renal disease progression deriving from aniform diabetic population.

The Modification of Diet in Renal DiseaseMDRD) Study provided the first evidence toupport a lower BP target in the appropriatehronic kidney disease population. In this study,atients with chronic kidney disease were ran-omly assigned to a low-BP group with a goalean BP of 92 mm Hg or less for patients 60

ears and younger and 98 mm Hg or less foratients older than 60 years and a group with aoal mean BP less than 107 mm Hg for patients0 years or younger and 113 mm Hg or less foratients older than 60 years. At the end of thetudy, patients with baseline proteinuria withrotein greater than 1,000 mg/d (�1 g/d) in theow-target group had a significant decrease inroteinuria and significantly slower decrease inFR compared with patients assigned to thesual-target group.29 Of note, proteinuria de-rease within the first 4 months of the study wasssociated with a slower subsequent decrease inFR. Moreover, analysis of data obtained aboutyears after the end of the randomization trial

howed that risks of kidney failure and the com-osite outcome of kidney failure and all-causeortality were significantly less in the low-

arget-BP group.28 In a recent meta-analysis oftudies of patients with nondiabetic kidney dis-ase, systolic BP of 110 to 129 mm Hg wasssociated with the lowest risk of kidney diseaserogression in patients with urine protein excre-ion greater than 1,000 mg/d (�1 g/d).30

Results of the African American Study ofidney Disease (AASK), which included Afri-

an-American patients with hypertensive kidneyisease, add support to the notion that patients

ith significant proteinuria benefit from a lower

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Antihypertensive Treatment in Proteinuria 15

P target. The overall trial showed that patientsandomly assigned to a lower mean BP targetess than 92 mm Hg derived no benefit from thisntervention in comparison to patients randomlyssigned to a usual target (mean BP, 102 to 107m Hg).31 However, a post hoc analysis of this

rial32 showed that baseline proteinuria was the keyactor that defined its results because the lower BParget preserved renal function in the small subsetf patients with proteinuria with protein greaterhan 1,000 mg/d (�1 g/d).

In patients with nondiabetic kidney diseasend lower urine protein levels, the evidence foruch a low BP goal is not as strong. In theDRD trial, no significant benefit in renal protec-

ion was apparent in the subgroup of patients withroteinuria less than 1,000 mg/d (�1 g/d) of pro-ein.29 In the cohort of patients with urine proteinxcretion less than 1,000 mg/d (�1 g/d) in theASK trial, there was a nonsignificant trend to-ard a slower decrease in GFR.31,32 That meta-

nalysis provided additional support of these find-ngs because it showed no significant associationetween systolic BP and risk of kidney diseaserogression in patients with proteinuria with pro-ein less than 1,000 mg/d (�1 g/d; Fig 1).30

The Ramipril Efficacy in Nephropathy (REIN)rial 2 has been considered as evidence to contra-ict low BP goals in patients with proteinuria.33

n this study, patients with nondiabetic nephropa-hy and urine protein excretion greater than 1,000

g/d (�1 g/d) already treated with the angioten-

in-converting enzyme (ACE) inhibitor ramiprilere assigned to either conventional (diastolicP � 90 mm Hg) or intensified (systolic/iastolic BP � 130/80 mm Hg) treatment withhe addition of the dihydropyridine calcium an-agonist felodipine. At the end of the treatmenteriod, cumulative incidence of ESRD, rate ofFR decrease, and residual proteinuria were

imilar in the 2 arms. However, this study wasnderpowered to detect a difference in decreasen GFR between the 2 BP groups because medianollow-up was only 1.6 years and there was only4.1/2.8–mm Hg difference in BP between treat-ent groups throughout the study.When all the evidence is pooled (Table 2), it is

lear that a BP goal less than 130/80 mm Hgefinitely must be sought, except for patientsith diabetes and those with nondiabetic chronicidney disease and proteinuria with proteinreater than 1,000 mg/d (�1 g/d). In patientsithout diabetes with proteinuria with proteinetween 300 and 1,000 mg/d (0.3 and 1 g/d),trong consideration also should be given for thisarget until specific trials clarify the issue.

TREATMENT OF HYPERTENSION ANDPRESERVING RENAL FUNCTION IN PATIENTS

WITH PROTEINURIA

onpharmacological Approaches

Overall, managing hypertension in Westernocieties on both sides of the Atlantic has proved

Figure 1. Relative risk ofkidney disease progressionbased on systolic BP and urineprotein excretion levels. Re-sults based on a meta-analysisof 11 randomized controlled tri-als. The reference group is de-fined at a systolic BP of 110 to

119 mm Hg. Modified from Ja-far et al.30

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ery difficult because control rates are only about0% in the United States and less than 10% ofhe overall hypertensive population in variousuropean countries.34 The presence of chronicidney disease makes hypertension managementven harder. Such lifestyle changes as weightoss, exercise, and alcohol moderation shouldave a central role in helping manage hyperten-ion in all patients, but low-protein diets, lowodium intake, and smoking cessation have beenroposed to have additional importance in termsf kidney function preservation and hyperten-ion control in patients with proteinuria.

The MDRD is the largest trial to date tovaluate the role of a low-protein diet for kidneyunction.35 The trial randomly assigned patientsith chronic kidney disease and proteinuria to 2P groups, as discussed previously, and either a

ow-protein (0.58 g/kg/d) or very-low-proteiniet (0.28 g/kg/d). The very-low-protein groupad a marginally (P � 0.07) slower decrease inFR than the low-protein group in 3 years,

ndicating a trend toward renal function preserva-ion when protein consumption decreases. Theseesults are strengthened by a meta-analysis show-ng that a low-protein diet reduces the decline inFR by 0.53 mL/min/y (0.01 mL/s/y).36 How-

ver, physicians must balance this benefit withhe difficulty that most patients have adhering tostrict diet restricting protein intake and must beigilant in monitoring patients for signs of malnu-rition.

Hypertension in patients with chronic kidneyisease is related to a large extent to salt sensitiv-ty. This was shown previously in a study compar-ng response to salt loading in patients withidney disease and healthy subjects. Both groupsere able to increase their fractional excretion of

odium after a salt load, but patients with

Table 2. Characteristics of Studies Evaluating t

M

ean follow-up (y)aseline GFR (mL/min/1.73 m2)aseline level of protein excretion (mg/d) 1ifference in renal outcomes betweenhigher and lower BP groups No d

Note: To convert GFR in mL/min to mL/s, multiply by 0.01*Subgroup analyses of these studies showed that patie

ecreases in GFR when BP less than 125/75 mm Hg is ach

idney disease also showed increases in BP.37 k

his was a result of the increase in extracellularolume caused by the high salt intake and inabil-ty of the impaired functioning kidneys to dealith this volume expansion. High dietary so-ium intake in patients with proteinuria is particu-arly deleterious for additional reasons. For ex-mple, the presence of a high salt load itself willncrease the oncotic pressure of the glomerularltrate, which leads to more protein pulled intorine.38 In addition, excessive dietary sodiumntake (ie, �6 g/d) will attenuate the effects ofany antihypertensive medications on protein-

ria reduction.39 Thus, recommending a dailyietary sodium intake of 2 to 4 g in patients withhronic kidney disease will help BP managementnd decrease urinary protein excretion.

Several population-based studies showed anssociation between smoking and both acceler-ted renal function decrease and increased risk ofeveloping abnormal UAE.40,41 The Heart Out-omes and Prevention Evaluation trial confirmedhis finding, showing a 20% greater risk of mi-roalbuminuria or proteinuria development inurrent smokers compared with nonsmokers.42

o date, no prospective trial examined the effectf smoking cessation on patients with renal dis-ase and proteinuria. However, on the basis ofhe cardiovascular benefits of smoking cessation,hysicians should recommend this interventiono patients with chronic kidney disease. That thislso will serve to decrease proteinuria and pre-erve renal function is possible, but remains to bestablished.

harmacological Therapy

Because the overall goal of hypertension man-gement in patients with nephropathy involvesot only decreasing BP to less than 130/80m Hg, but also slowing the progression of

act of Different BP Levels on Renal Outcomes

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Antihypertensive Treatment in Proteinuria 17

ular disease, physicians must be aware of theresence of proteinuria and use antihypertensivegents that also decrease it because this willesult in better renal and cardiovascular out-omes.43

ACE InhibitorsAntihypertensive agents that interfere with the

enin-angiotensin-aldosterone system, ie, ACEnhibitors and angiotensin receptor blockersARBs), are those most consistently found toecrease proteinuria and the rate of renal func-ion deterioration in patients with diabetic andondiabetic kidney disease, independent of BPevels. For ACE inhibitors, this was shown first inhe original trial of the Collaborative Study Grouphat randomly assigned 409 patients with type 1iabetes with overt nephropathy (UAE � 500 mg/d�0.5 g/d]) and mild renal insufficiency (serumreatinine � 2.5 mg/dL [�221 �mol/L]) to capto-ril or placebo therapy44 (Table 3). After a me-ian follow-up of 3 years, treatment with capto-ril led to a 43% decrease in risk of the primarynd point of doubling of serum creatinine level;0% decrease in the combined end points ofeath, need for dialysis therapy, and transplanta-ion; and 30% decrease in UAE in comparison tolacebo. Although there were small differencesn BP between the 2 groups, these effects werendependent of BP levels.

Subsequent studies supported the use of ACEnhibitors to decrease proteinuria and preserveenal function in patients with nondiabetic kid-ey disease. In the first report of the REIN Study,n patients without diabetes with an averagereatinine level of 2.4 mg/dL (212.4 �mol/L)nd 24-hour urine protein excretion greater than,000 mg/d (�3 g/d) randomly assigned toamipril, 5 mg/d, or placebo, ramipril was associ-ted with a 55% decrease in median urine proteinxcretion from baseline and significant decreasesn UAE, GFR decline, and risk of doubling oferum creatinine level or progressing to ESRDompared with placebo. The risk of kidney diseaserogression still decreased significantly after adjust-ent for changes in systolic and diastolic BP.45 In

he AASK trial, African-American patients withypertensive kidney disease, a mean serum creati-ine level of 2.2 mg/dL (194.7 �mol/L), and 24-our urine protein excretion of 600 mg/d (0.6

/d) were randomly assigned to ramipril, amlo- o

ipine, or metoprolol. Patients treated withamipril had a 36% decrease in the secondaryomposite outcome of 50% decrease in GFR,SRD, or death compared with amlodipine and a2% decrease compared with metoprolol.31 Arevious meta-analysis of patients with nondia-etic chronic kidney disease showed that regi-ens including an ACE inhibitor were associ-

ted with a 31% decrease in progression toSRD and 30% decrease in the combined endoint of doubling of serum creatinine level orrogression to ESRD.46 Finally, in a recent studyn which 224 patients with serum creatinineevels of 3.1 to 5.0 mg/dL (274.3 to 442.5mol/L) and persistent proteinuria (mean urinerotein excretion, 1,600 mg/d [1.6 g/d]) wereandomly assigned to administration of 20 mg/df benazepril or placebo on top of conventionalntihypertensive therapy,47 benazepril was asso-iated with a 43% decrease in risk of the primarynd point (doubling of serum creatinine level,SRD, or death), 23% decrease in rate of decline

n renal function, and 2.5 times greater decreasen proteinuria compared with placebo after aean follow-up of 3.4 years, benefits that did not

eem attributable to better BP control.In contrast to these results, findings from more

ecent studies suggest that the only benefit seenith ACE inhibitors is related to BP decrease.or example, in the UKPDS 39, captopril andtenolol had similar outcomes on microvascularnd macrovascular complications in hyperten-ive patients with type 2 diabetes.48 Well-ontrolled animal studies,49 post hoc data fromhe Antihypertensive and Lipid-Lowering Treat-ent to Prevent Heart Attack Trial (ALLHAT),50

nd a recent meta-analysis51 expanded the ideahat ACE inhibitors have no unique effects inde-endent of BP decrease for patients with nondia-etic kidney disease. As in the total population ofLLHAT,52 in patients with a mild (60 to 89L/min/1.73 m2 [1.00 to 1.48 mL/s/1.73 m2]) oroderate-severe (�60 mL/min/1.73 m2 [�1.00L/s/1.73 m2]) decrease in baseline GFR, thereere no differences in incidence of ESRD or a0% or greater decrease in GFR between theroups of chlorthalidone, amlodipine, and lisino-ril.50 In the meta-analysis of Casas et al,51 usef ACE inhibitors or ARBs was shown not to beelated to an additional BP decrease, lower risk

f doubling of serum creatinine level, or inci-

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ence of ESRD in patients with diabetic nephrop-thy. In patients with nondiabetic kidney, thesegents were associated with BP-independentmall renal benefits, which were proposed to bencertain because of evidence of small-study

Table 3. Long-Term Studies of AntihypertensivRenal

Regimens ComparedNo. of

PatientsBaseline G

(mL/min/1.7

iabetic nephropathyCaptopril trial, 199344 Captopril v placebo 409 68

Bakris et al, 199665 Lisinopril v non-DHPCCBv atenolol

52 59

Bakris et al, 199766 Verapamil SR v atenolol 34 62

Smith et al, 199867 Diltiazem v nifedipineGITS

21 96

RENAAL, 200159 Losartan v placebo 1,513 54

IDNT, 200160 Irbesartan v amlodipine vplacebo

1,715 59

REIN-2, 200533 Conventional v intensifiedcontrol

338 35

ondiabetic kidneydisease

MDRD, 1994(Study B)29

Usual v low BP goal 255 20

AIPRI, 199653 Benazepril v placebo 583 42

REIN, 199745 Ramipril v placebo 166 39

AASK, 200131 Metoprolol v amlodipine vramipril; usual v low BPgoal

1,094 46

Hou et al, 200647 Benazepril v placebo 224 26

Note: To convert GFR in mL/min to mL/s, multiply by 0.01Abbreviations: AIPRI, Angiotensin-Converting-Enzyme I

elease; GITS, gastrointestinal transcapillary system.*Urinary albumin-creatinine ratio in grams per gram.†Median follow-up.‡Median follow-up changing for the various comparisons

ias. i

The lack of benefit seen with ACE inhibitorsn these later cases relates to several issues. Mostmportantly, it seems that baseline UAE levelnd stage of kidney disease are key factors deter-ining benefit from treatment with an ACE

ment in Patients With Proteinuria With Primaryoints

Baselineroteinuria

(g/d)Mean

Follow-Up Main Findings

1.2 3 y Captopril led to 43% reduction in risk of doubling ofserum creatinine level; 50% reduction incombined end point of death, need for dialysis,and transplantation; and 30% reduction inproteinuria compared with placebo

3.5 63 mo No difference in decrease in creatinine clearancebetween lisinopril and non-DHPCCB groups,significantly greater decrease in atenolol group

3.2 54 mo Verapamil SR associated with slower rate ofdecrease in creatinine clearance and greaterreduction in proteinuria compared with atenolol

0.9 21 mo Diltiazem associated with 57% reduction inbaseline proteinuria, whereas nifedipine GITS‡produced no change

1.25* 3.4 y Losartan associated with 16% reduction in risk ofdoubling of baseline serum creatinine level,progression to ESRD, or death and 35%reduction in albumin-creatinine ratio comparedwith placebo

2.9 2.6 y Irbesartan associated with 20% reductioncompared with placebo and 23% reductioncompared with amlodipine in risk of doubling ofbaseline serum creatinine level, progression toESRD, or death and 33% reduction inproteinuria from baseline

2.9 19 mo† No difference in renal outcomes

1.45 2.2 y Patients with baseline proteinuria � 1 g/d in thelow-goal group had slower GFR decrease anddecrease in proteinuria compared with those inusual-goal group

1.8 3 y Benazepril associated with 53% reduction in risk ofdoubling of serum creatinine level or ESRDcompared with placebo

5.3 16 mo Ramipril associated with significant reductions inUAE, GFR decrease, and risk of doubling ofserum creatinine level or progressing to ESRDcompared with placebo

0.5 3-4.1 y Ramipril associated with 36% reduction insecondary composite outcome of 50% decreasein GFR, ESRD, or death compared withamlodipine and 22% reduction compared withmetoprolol

Patients with baseline proteinuria �1 g/d in thelow-goal group had slower GFR declinecompared with those in usual-goal group

1.6 3.4 y Benazepril associated with 43% reduction in risk ofdoubling of serum creatinine level, ESRD, ordeath; 23% decrease in rate of GFR decline;and 2.5 times greater reduction in proteinuriacompared with placebo

n in Progressive Renal Insufficiency Study; SR, sustained

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Antihypertensive Treatment in Proteinuria 19

rovides some of the strongest evidence to sup-ort this idea because patients in that study withserum creatinine level greater than 2.0 mg/dL

�177 �mol/L) derived the greatest benefit fromdding renin-angiotensin-aldosterone system in-ibition to a standard antihypertensive regimenecause those in the ACE-inhibitor group had a4% decrease in risk of doubling of serum creat-nine level compared with the placebo group.onversely, only a 4% reduction in this end pointas seen with ACE inhibition in patients with a

erum creatinine level less than 1.0 mg/dL (�88.5mol/L).44 In a previous study of benazepril inatients with kidney disease of various causes,he reduction in the primary end point (doublingf serum creatinine level or need for dialysisherapy) was greater in those with baseline uri-ary protein excretion greater than 1,000 mg/d�1 g/d).53 In the REIN Study, a higher degreef baseline urinary protein excretion was associ-ted with larger differences in the mean rate ofFR decrease and the percentage of patients

eaching the combined end point (doubling oferum creatinine level or ESRD) between thelacebo and ramipril groups.45 Similarly, theentioned meta-analysis of nondiabetic renal

isease30 showed a better renoprotective actionf ACE inhibitors in patients with greater levelsf proteinuria.In addition, because proteinuria clearly is asso-

iated with increased risk of nephropathy progres-ion, a decrease in UAE in proteinuric patientshould be related to preservation of renal func-ion. In the REIN trial, the percentage of de-rease in proteinuria correlated inversely withecrease in GFR and predicted the decrease inisk of doubling of baseline creatinine level orSRD. As mentioned, the decrease in risk of

enal disease progression was independent of BPhanges, but after adjustment for changes inroteinuria, it was no longer significant.45 In theASK, although only 33% of participants hadroteinuria at baseline, a decrease in proteinuriaarly in the disease course (6 months) predictedSRD development at 5 years.32 This was con-rmed from other 2 post hoc analyses of largeutcome trials using ARBs,54,55 discussed next.n ALLHAT, UAE measurements did not takelace.50 Thus, it is difficult to interpret the lackf selective benefit of ACE-inhibitor treatment

n this trial. In addition, exclusion criteria in d

LLHAT included heart failure, serum creatinineevel in excess of 2.0 mg/dL (�177 �mol/L), andurrent treatment with an ACE inhibitor for un-erlying kidney disease, and, according to Rah-an et al,50 presumably participants with de-

reased renal function mostly were patients withschemic renal disease, for which an overwhelm-ng renoprotective effect of ACE inhibitors isot expected. With regard to the meta-analysisf Casas et al,51 a great influence of the magni-ude of ALLHAT as well as a number ofethod issues (ie, selection of renal outcomes

o be analyzed, ignorance of the previouslyentioned issue of proteinuria) recently were

roposed to severely hamper relevant conclu-ions.56

The Microalbuminuria, Cardiovascular, andenal Outcomes substudy of the Heart Out-omes Prevention study showed that adding anCE inhibitor to the antihypertensive regimen inatients at high risk of cardiovascular events notnly decreased the risk of developing overt ne-hropathy, but also decreased cardiovascular out-omes. The ramipril group had a 25% reductionn the primary outcome (myocardial infarction,troke, or cardiovascular death) compared withhe placebo group.57 The risk of cardiovascularvents increased almost linearly as UAE in-reased, and risk reduction from using an ACEnhibitor is more pronounced the higher the levelf UAE.58

Overall, it seems that ACE inhibitors have anmportant renoprotective effect in addition to BPeduction in patients with proteinuria and ad-anced kidney disease (ie, stage 3 or higherephropathy). The higher the degree of baselinerine protein excretion and proteinuria decrease,he more pronounced the effect.

Angiotensin Receptor BlockersARBs are a newer class than ACE inhibitors;

herefore, data involving ARBs are less abun-ant. Two large renal outcome trials, the Reduc-ion of Endpoints in Non-insulin dependent dia-etes mellitus with the Angiotensin II Antagonistosartan (RENAAL) trial59 and the Irbesartan iniabetic Nephropathy Trial (IDNT),60 showed

hat ARBs also have renoprotective propertieseyond their effect on BP. The RENAAL trialandomly assigned 1,513 patients with type 2

iabetes with a mean creatinine level of 1.9

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Sarafidis, Khosla, and Bakris20

g/dL (168 �mol/L) and median albumin-reatinine ratio of 1,237 mg/g (1.237 g/g) to theRB losartan or placebo. After a mean follow-upf 3.4 years, losartan treatment was associatedith a 16% reduction in the primary end point ofoubling of baseline serum creatinine level, pro-ression to ESRD, or death; 35% decrease inlbumin-creatinine ratio; and 15% decrease inate of decline in estimated creatinine clear-nce.59 Subsequently, it was sought to determinehether there was an association between base-

ine proteinuria, initial decrease in proteinuria, oregree of residual proteinuria and the combinedrimary end point. Baseline proteinuria level hadnearly linear relationship with risk of achieving

he primary outcome. More importantly, the trialhowed that for every 50% decrease in albumin-ria in the first 6 months after initiating treatmentith losartan, there was a 36% risk reduction of

he primary end point and 45% reduction forSRD at trial end. The decrease in proteinuria

n the first 6 months of therapy mirrored theearly linear relationship between baseline pro-einuria and renal risk.54 Interestingly, it wasstimated that losartan could delay the needor dialysis therapy or transplantation for 2ears, and the investigators concluded that allenoprotection from losartan use was attrib-ted to antiproteinuric effect of the ARB andas not related to BP.54

In the IDNT, 1,715 patients with type 2 diabe-es with a mean serum creatinine level of 1.7g/dL (150.5 �mol/L) and median urinary pro-

ein excretion of 2,900 mg/d (2.9 g/d) wereandomly assigned to irbesartan, amlodipine, orlacebo. The primary end point was the same asith RENAAL. Treatment with irbesartan re-

ulted in a 20% reduction compared with pla-ebo and 23% reduction compared with amlodip-ne in the primary composite outcome after aean follow-up of 2.6 years, whereas proteinuria

ecreased by 33% in the irbesartan group versus% in the amlodipine group and 10% in thelacebo group.60 This study also confirmed theelationship between baseline proteinuria andisk of renal disease progression because ithowed that for every 2-fold increase in baselineroteinuria level, risk of reaching the primarynd point doubled. Irrespective of treatmentroup, this risk was cut in half with every 50%

ecrease in proteinuria at 1 year. However, after p

year of treatment, 40% of patients in therbesartan group had a greater than 50% decreasen proteinuria compared with 20% in the amlodip-ne group and 25% in the placebo group. Again,he investigators of this trial attribute the supe-ior renoprotective effect of irbesartan to itsntiproteinuric properties.55

A recent post hoc analysis of data from theosartan Intervention for Endpoint Reduction inypertension Study showed that UAE decreaseith an ARB is related to a decrease in cardiovas-

ular disease risk.61 The study population ofore than 8,000 patients with hypertension and

eft ventricular hypertrophy followed up for aean of 4.8 years was stratified into groups by

aseline UAE level. Of note, whereas a smallercentage of patients in this trial had overtroteinuria, the majority of participants had mi-roalbuminuria. Analysis showed that those withhe highest baseline UAE had a 3- to 4-foldreater risk of reaching the primary cardiovascu-ar end point of first occurrence of cardiovasculareath, nonfatal stroke, and nonfatal myocardialnfarction compared with those in the lowest-AE group. The extent of UAE decrease at 5ears predicted the risk reduction for the primarynd point.61

In summary, it would appear that ACE inhibi-ors and ARBs provide similar cardiovascularnd renal protection. This similarity was sup-orted by the Diabetics Exposed to Telmisartannd Enalapril Study, which compared the effectsf enalapril and telmisartan in 250 patients withype 2 diabetes, hypertension, and UAE between1 and 999 �g/min (19 � 10�8 and 17 � 10�6

/s). After 2 years of follow-up, the 2 agents hadimilar effects on change in GFR, serum creati-ine level, UAE, BP, and rates of ESRD, cardio-ascular events, and death from all causes.62

owever, there are some who call for the use ofRBs in place of ACE inhibitors because theyenerally are better tolerated, have a lower inci-ence of hyperkalemia and cough, and are notssociated with the life-threatening complicationf angioedema.63 The greater cost of ARBs makeshis argument untenable for some, but ARBsere proved to be cost-effective in the manage-ent of nephropathy in various settings.64 Over-

ll, it is reasonable to use the 2 classes inter-hangeably in patients with proteinuria in clinical

ractice.

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Antihypertensive Treatment in Proteinuria 21

Calcium Channel BlockersThe 2 different subtypes of calcium channel

lockers, nondihydropyridine (non-DHPCCB)nd dihydropyridine (DHPCCB), were shown toave divergent effects on patients with highevels of proteinuria. In previous studies of pa-ients with overt diabetic nephropathy, non-HPCCBs (verapamil, diltiazem) were associ-

ted with decreases in proteinuria and rate ofreatinine clearance decline that were greaterhan those with atenolol65,66 and no differentrom those with lisinopril,65 with similar BPontrol in the various groups. In another cohortf patients with diabetic nephropathy followedp for 21 months, a DHPCCB, nifedipine XL,roduced no change in proteinuria, whereas dilti-zem resulted in a proteinuria decrease of about0%.67 The mechanism for this difference relateso the more pronounced impairment in renalutoregulation and glomerular pressure transmis-ion produced by DHPCCBs.68 This relates toncreased renal blood flow and gives the mis-aken impression of preserved renal function, butomes at the expense of additional increasedntraglomerular pressures and permeability tolbumin, which, in turn, leads to poorer renalutcomes.Additional evidence to support a lack of reno-

rotective properties of DHPCCBs comes fromulticenter trials. As mentioned, in the IDNT,

mlodipine was associated with a 6% increase inroteinuria versus baseline and 23% greater inci-ence of the primary end point of doubling oferum creatinine level, onset of ESRD, or deathompared with irbesartan.60 In the nondiabeticopulation of the AASK trial, the 58% increasen proteinuria at 6 months in those treated withmlodipine correlated with a greater incidence ofhe composite end point of a 50% or greaterecrease in GFR, ESRD, and/or death comparedith those treated with ramipril, who had a 20%ecrease in proteinuria.31 Data from the REIN-2tudy lead to questions about the ability ofHPCCBs to help toward regression of renal

unction deterioration in patients with protein-ric kidney disease, even by means of BPecrease, but need to be confirmed from addi-ional studies with longer follow-up.33

It has to be noted that these clear differences

etween effects of calcium channel blocker sub- t

lasses on the kidney seem to manifest only inatients with advanced disease with protein-ria.69 In ALLHAT, there were no differences inncidence of ESRD or a 50% or greater decreasen GFR among the groups administered chlortha-idone, amlodipine, and lisinopril.50,52 However,his finding is not very informative because UAEas not measured, as discussed. The total num-er of participants with kidney disease and heavyroteinuria are unknown; however, it must haveeen small because exclusion criteria in ALLHATncluded serum creatinine level in excess of 2.0g/dL (�177 �mol/L) and current treatmentith an ACE inhibitor for underlying kidneyisease. In the hypertensive Appropriate Bloodressure Control in Diabetes trial,70 in which70 hypertensive subjects were randomly as-igned to nisoldipine or enalapril treatment, thereas no difference in creatinine clearances be-

ween the 2 groups during 5.3 years of follow-up,lthough enalapril significantly decreased preex-sting levels of microalbuminuria. However, al-ost all participants had normoalbuminuria oricroalbuminuria, not microalbuminuria. More-

ver, baseline mean creatinine clearance was 84L/min/1.73 m2 (1.40 mL/s/1.73 m2) in the

verall population and about 75 mL/min/1.73 m2

1.25 mL/s/1.73 m2) in the subgroup of patientsith macroalbuminuria. This is far better kidney

unction than any trial showing a benefit withenin-angiotensin system blockade. Moreover,he most definite end point of ESRD incidenceas not recorded.The issues mentioned also were exemplified

y data resulting from the Bergamo Nephrologiciabetes Complications Trial, which compared

he effect of a non-DHPCCB and an ACE-nhibitor, alone or in combination, on microalbu-inuria development in a group of hypertensive

ormoalbuminuric patients with type 2 diabetes.fter a median follow-up of 3.6 years, progres-

ion to microalbuminuria was significantly lessn subjects treated with trandolapril or the combi-ation (6.0% and 5.7%, respectively) comparedith subjects receiving verapamil or placebo

11.9% and 10.0%, respectively).71 Overall, theseotions are in keeping with the mentioned obser-ations about ACE inhibitors, ie, in patients withdvanced kidney disease with proteinuria, theocus should be both BP and proteinuria reduc-

ion with the use of proper agents, whereas in

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hose with early kidney disease, the focus shoulde BP control and cardiovascular risk reduction.

DiureticsThiazide diuretics have not been shown to

ecrease urine protein excretion beyond themount expected because of BP reduction. How-ver, because most patients with chronic kidneyisease and proteinuria would need a combina-ion of 2 or more antihypertensive agents toeach the mentioned BP goals and renal functioneterioration is accompanied by salt and wateretention, the National Kidney Foundation–idney Disease Outcomes Quality Initiativeuidelines suggest that if BP is not controlled, aiuretic should be the first agent to add to anCE inhibitor or ARB in patients with protein-ria.2 It has to be noted that thiazide diureticsecome less effective when GFR decreases toess than 40 mL/min/1.73 m2 (�0.67 mL/s/.73 m2),72 and to control BP in patients with aFR less than that level, a loop diuretic (ie,

urosemide, torsemide, and so on) is very likelyo be needed. If furosemide is used, it should beosed adequately (ie, 2 to 3 times instead of onceaily) because it has a very short duration ofction (3 to 6 hours). Recent data suggest thatse of such aldosterone receptor antagonists aspironolactone and eplerenone in low doses maye indicated in patients with proteinuric kidneyisease, discussed in detail next. However, potas-ium-sparing diuretics should be avoided inatients with preexisting hyperkalemia, ie, se-um potassium level greater than 5.5 mEq/L�5.5 mmol/L), from either diabetes or renalisease from other causes, and, when used, se-um potassium level must be followed up closelynd a dose adjustment of the concomitant conven-ional diuretic therapy always should be consid-red.

�-BlockersIn general, there is no direct evidence that

onventional �-blockers provide additional reno-rotective effects. As mentioned, studies of pa-ients with overt diabetic nephropathy showedhat non-DHPCCBs produced significant de-reases in proteinuria and rate of creatinine clear-nce decline compared with atenolol.38,65 In pa-ients with type 2 diabetes in the UKPDS 39

tudy, there were no significant differences be- 3

ween captopril and atenolol in level of BPchieved, incidence of overt nephropathy, andate of plasma creatinine level doubling, datauggesting that any renoprotective effect is causedy BP lowering.48 Therefore, �-blockers wereuggested to be used in patients with proteinurias third-line agents to achieve BP control.2 How-ver, recent data from the Glycemic Effects iniabetes Mellitus: Carvedilol-Metoprolol Com-arison in Hypertensives trial showed that 1 ofhe newer �-blockers, carvedilol, was associatedith significant reductions in risk of microalbu-inuria development in hypertensive patientsith type 2 diabetes compared with metopro-

ol.73 These findings call for a prospective trialxamining the effect of this drug in patients withenal disease and proteinuria.

�-BlockersAlthough combining effective BP reduction74

nd a beneficial metabolic profile,75 �-blockersere not shown to slow renal disease progres-

ion or decrease UAE in patients with type 2iabetes and albuminuria.76 Moreover, this classf agents also failed to decrease cardiovascularvents in patients who had or developed heartailure, evidenced by results of the long-acting-blocker arm of ALLHAT, which was stoppedarly because of an increased incidence of heartailure.77 Hence, this class should not be pre-erred as initial or even second-line treatment forypertension in patients with chronic kidneyisease, but as third-line treatment, especially inlder men with benign prostatic hypertrophy andrine flow problems.78

Combination Therapy Approaches toecrease ProteinuriaIn addition, recent data suggest that specific

ombinations of antihypertensive agents can beven more effective in proteinuria reduction. Forxample, combined use of ACE inhibitors andRBs was shown to decrease proteinuria and

low kidney disease progression more effec-ively than using ACE inhibitors or ARBs alone.n the Combination Treatment of ARB and ACE-nhibitor in Non-diabetic Renal Disease trial,63 patients with nondiabetic kidney disease andean urinary protein excretion of 2,500 mg/d

2.5 g/d) were randomly assigned to trandolapril,

mg/d; losartan, 100 mg/d; or a combination of

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Antihypertensive Treatment in Proteinuria 23

he 2 drugs at the same dosages. After 3 years ofollow-up, urinary protein excretion decreasedignificantly more with combined therapy75.6%) compared with trandolapril (44.3%) orosartan (44.1%) alone. Moreover, the group ofatients treated with combined therapy had a0% to 62% decrease in the primary end point ofime to doubling of serum creatinine level orSRD compared with either the trandolapril- or

osartan-treated group.79 It is important to notehat these findings were independent of BP differ-nces because both office and ambulatory BPecreases were similar across all 3 groups.80 Inddition, patients with the greatest decreases inroteinuria at 6 months had the slowest de-reases in GFR,80 a finding also supporting themportance of proteinuria reduction for kidneyunction preservation. Other studies and a meta-nalysis further support the notion that the com-ination of ACE inhibitors and ARBs is notuch use for BP decrease in patients with uncom-

licated hypertension, but can be beneficial forroteinuria reduction.81,82

Another useful combination could be the addi-ion of an aldosterone receptor antagonist toatients already administered an ACE inhibitorr an ARB, keeping in mind the attention neededo be given to potassium levels, as discussed. Theationale for such a combination is that plasmaldosterone levels increase in patients withhronic kidney disease and may contribute toenal injury,83 whereas blockade of the renin-ngiotensin-aldosterone system with ACE inhibi-ors or ARBs does not necessarily result in aaintained decrease in plasma aldosterone lev-

ls.84 The addition of spironolactone in protein-ric patients already administered an ACE inhib-tor or an ARB decreased proteinuria in pilottudies.85-88 Moreover, eplerenone, the newerldosterone receptor antagonist, further reducedAE in patients with hypertension and left ven-

ricular hypertrophy when added to an ACEnhibitor.89 Larger future studies are needed toonfirm these promising findings.

Combining an ACE inhibitor and a non-HPCCB previously was shown to decreaseroteinuria. The first study to evaluate this com-ination included 30 patients with type 2 diabe-es and renal insufficiency who were randomlyssigned to receive either lisinopril alone, vera-

amil alone, a combination of the 2, or hydrochlo- t

othiazide and guanfacine for 1 year. Patientsreated with the combination had a 78% decreasen albuminuria compared with a 59% decrease inhose treated with lisinopril alone.90 Also ofote, patients receiving the combination therapyad the best side-effect profile of any of theroups. This likely occurred because combininghe 2 medications allowed for lower doses ofach to be used. However, in a more recent studyf 69 patients with nondiabetic nephropathy, theddition of verapamil to trandolapril treatmentid not significantly affect proteinuria after 8onths.91 Thus, this issue needs to be examined

urther.

CONCLUSION

Proteinuria is a well known risk factor for therogression of renal disease and cardiovascularorbidity and mortality. To maximize risk reduc-

ion, physicians must focus on achieving a targetP less than 130/80 mm Hg in those with UAEreater than 300 mg/d (�0.3 g/d). ACE inhibi-ors and ARBs should be used as first-line antihy-ertensive therapy in patients with proteinuriaecause these classes have a BP-independentntiproteinuric effect and consistently were showno improve renal and cardiovascular outcomes. IfP levels are still out of goal, initially a thiazider a loop diuretic and then compounds from thether antihypertensive classes should be added tochieve BP control. Combination therapy withn ACE inhibitor and an ARB or, in addition touch agents, a non-DHPCCB or an aldosteronentagonist should be considered if the degree ofroteinuria is still high. Overall, physicians mustake aggressive measures to decrease both BPnd proteinuria to give their patients maximalenal and cardiovascular protection.

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Antihypertensive Treatment in Proteinuria 25

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